The use of immune checkpoint inhibitors that bind immune checkpoint molecules such as programmed death 1 (PD-1), programmed death ligand-1 (PD-L1), cytotoxic T-lymphocyte-associated antigen (CTLA-4), or V-domain Ig suppressor of T cell activation (VISTA) and cause immune checkpoint blockade is a promising approach being investigated for the treatment of cancer and infectious diseases. Despite impressive therapeutic responses in clinical trials in a large number of cancers, not all subjects with those cancers respond to immune checkpoint blockade. In addition, there are many cancers for which a therapeutic response to treatment with antibodies that bind immune checkpoint molecules (e.g., PD-1 or CTLA-4) has not been evident.
Enhancing CD4 and CD8 T cell activity against a variety of cells, including cancer cells, is another approach being investigated to treat cancers and infectious diseases. In one strategy, T lymphocytes are stimulated with antigen, expanded ex-vivo, and then transfused into a subject. This is a form of adoptive cellular therapy (ACT). Certain ACT strategies have been shown in early stage clinical trials to induce cancer regression. ACT may be particularly useful in treating cancers and/or infectious diseases that arise following immune-ablation and hematopoietic stem cell transplantation (HSCT).
Still another approach being investigated for treating cancer is hematopoietic stem cell transplantation (HSCT) and/or hematopoietic stem cell (HSC) mobilization. HSCT and/or HSC mobilization, when combined with treatments to induce mild lymphopenia, may enhance the effects of certain cell based immunotherapies.
Immune checkpoint blockade alone, e.g., anti-PD1, anti-PD-L1, anti-CTLA-4, or anti-VISTA mediated blockade, and the administration of HSCs or an HSC mobilizing agent alone, do not show clinical effects in many subjects with different cancers. However, it has been discovered according to the present disclosure that the combination of HSC transfer with immune checkpoint blockade (e.g., anti-PD-1 mediated blockade or anti-VISTA mediated blockade), is synergistic in the treatment of cancer. This synergy allows for the treatment of a cancer that is refractory to immune checkpoint blockade by treatment with an immune checkpoint inhibitor and HSC transplantation, and can result in significant long-term regression of a checkpoint inhibitor-resistant cancer. The discovery of the present disclosure that combination treatment with an anti-PD-1 antibody and hematopoietic stem cell transplantation reverses resistance to immune checkpoint blockade using anti-PD-1 antibody monotherapy was verified in multiple brain tumor models (e.g., brain stem glioma, cortical glioblastoma, and medulloblastoma).